title: The genotype of early-transmitting HIV gp120s promotes α (4) β(7)-reactivity, revealing α (4) β(7) +/CD4+ T cells as key targets in mucosal transmission.
abstract: Mucosal transmission of HIV is inefficient. The virus must breach physical barriers before it infects mucosal CD4+ T cells. Low-level viral replication occurs initially in mucosal CD4+ T cells, but within days high-level replication occurs in Peyer's patches, the gut lamina propria and mesenteric lymph nodes. Understanding the early events in HIV transmission may provide valuable information relevant to the development of an HIV vaccine. The viral quasispecies in a donor contracts through a genetic bottleneck in the recipient, such that, in low-risk settings, infection is frequently established by a single founder virus. Early-transmitting viruses in subtypes A and C mucosal transmission tend to encode gp120s with reduced numbers of N-linked glycosylation sites at specific positions throughout the V1-V4 domains, relative to typical chronically replicating isolates in the donor quasispecies. The transmission advantage gained by the absence of these N-linked glycosylation sites is unknown. Using primary α₄β₇/CD4+ T cells and a flow-cytometry based steady-state binding assay we show that the removal of transmission-associated N-linked glycosylation sites results in large increases in the specific reactivity of gp120 for integrin-α₄β₇. High-affinity for integrin α₄β₇, although not found in many gp120s, was observed in early-transmitting gp120s that we analyzed. Increased α₄β₇ affinity is mediated by sequences encoded in gp120 V1/V2. α₄β₇-reactivity was also influenced by N-linked glycosylation sites located in C3/V4. These results suggest that the genetic bottleneck that occurs after transmission may frequently involve a relative requirement for the productive infection of α₄β₇+/CD4+ T cells. Early-transmitting gp120s were further distinguished by their dependence on avidity-effects to interact with CD4, suggesting that these gp120s bear unusual structural features not present in many well-characterized gp120s derived from chronically replicating viruses. Understanding the structural features that characterize early-transmitting gp120s may aid in the design of an effective gp120-based subunit vaccine.
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Fatima
authors.initials: F
authors.lastname: Nawaz
authors.forename: Claudia
authors.initials: C
authors.lastname: Cicala
authors.forename: Donald
authors.initials: D
authors.lastname: Van Ryk
authors.forename: Katharine E
authors.initials: KE
authors.lastname: Block
authors.forename: Katija
authors.initials: K
authors.lastname: Jelicic
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: McNally
authors.forename: Olajumoke
authors.initials: O
authors.lastname: Ogundare
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Pascuccio
authors.forename: Nikita
authors.initials: N
authors.lastname: Patel
authors.forename: Danlan
authors.initials: D
authors.lastname: Wei
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Fauci
authors.forename: James
authors.initials: J
authors.lastname: Arthos
mesh_terms: D000595:Amino Acid Sequence; D057134:Antibodies, Neutralizing; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D002478:Cells, Cultured; D005434:Flow Cytometry; D005838:Genotype; D006031:Glycosylation; D006678:HIV / Q000235:genetics*; D015699:HIV Envelope Protein gp120 / Q000235:genetics* / Q000378:metabolism; D015658:HIV Infections / Q000635:transmission* / Q000821:virology; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000821:virology*; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D020349:Surface Plasmon Resonance
chemical_list: D057134:Antibodies, Neutralizing; D015699:HIV Envelope Protein gp120; D016023:Integrins; C071777:integrin alpha4beta7